DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for X-linked Alport syndrome — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleX-linked Alport syndrome maps to a 5-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for x-linked alport syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
collagen type IV alpha 5 chain (COL4A5) — COL4A5 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet pgedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6WKU · 1.76 Å · ligand TRIETHYLENE GLYCOL (PGE). Experimental structure, not a prediction.
What the evidence adds up to
In a 2009 mouse study of X-linked Alport syndrome, female carriers of a Col4a5 mutation were bred to differ only in the X-controlling element that regulates X-inactivation. Those with preferential inactivation of the mutant Col4a5 gene showed improved survival and better surrogate outcomes for urine protein and plasma urea nitrogen up to 6 months of age. The degree of X-inactivation in kidney tissue, measured by allele-specific mRNA assays, correlated with these surrogate measures. The authors concluded that X-inactivation is a major modifier of the carrier phenotype in this model.
A 2021 study generated a mouse model carrying the frameshift variant c.980_983del ATGG in Col4a5, identified in a male patient with X-linked Alport syndrome. The paper does not report any treatment or survival data from these mice; it states only that a model was needed to explore pathogenesis and progression of that specific variant.
A 2023 retrospective study of 128 Chinese children from 126 families diagnosed with Alport syndrome between 2003 and 2021 found that X-linked forms accounted for 77.0% of families, autosomal recessive for 11.9%, autosomal dominant for 7.1%, and digenic for 4.0%. Among the patients, 59.4% were male and 40.6% female. Whole-exome sequencing identified 114 different mutations in 101 patients from 99 families; 68 of those mutations had not been previously reported. Glycine substitution was the most common mutation type, found in 52.1% of X-linked, 36.7% of autosomal recessive, and 60% of autosomal dominant cases. After a median follow-up of 3.3 years, kidney survival was significantly lower in autosomal recessive Alport syndrome than in X-linked Alport syndrome (P = 0.004). Extrarenal involvement was rare in these paediatric patients.
No drug treatment was tested in any of these studies. The 2009 mouse work suggests that manipulating X-inactivation patterns might be a strategy for symptomatic female carriers, but no such intervention has been developed or tested in humans. The 2023 cohort provides natural history data but no randomised trial, no biomarker that predicts individual progression, and no therapy. What is still missing is a clinical trial that tests a drug in X-linked Alport syndrome patients, adequate funding for such a trial, and a method to stratify patients by X-inactivation pattern or mutation type before treatment begins.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome
AbstractBACKGROUND: Female carriers of X-linked Alport syndrome (XLAS) demonstrate variability in clinical phenotype that, unlike males, cannot be correlated with genotype. X-inactivation, the method by which females (XX) silence transcription from one X chromosome in order to achieve gene dosage parity with males (XY), likely modifies the carrier phenotype, but this hypothesis has not been tested directly. METHODS: Using a genetically defined mouse model of XLAS, we generated two groups of Alport female (Col4a5(+/-)) carriers that differed only in the X-controlling element (Xce) allele regulating X-inactivation. We followed the groups as far as 6 months of age comparing survival and surrogate outcome measures of urine protein and plasma urea nitrogen. RESULTS: Preferential inactivation of the mutant Col4a5 gene improved survival and surrogate outcome measures of urine protein and plasma urea nitrogen. In studies of surviving mice, we found that X-inactivation in kidney, measured by allele-specific mRNA expression assays, correlated with surrogate outcomes. CONCLUSIONS: Our findings establish X-inactivation as a major modifier of the carrier phenotype in X-linked Alport syndrome. Thus, X-inactivation patterns may offer prognostic information and point to possible treatment strategies for symptomatic carriers.
Clinical, histological and molecular characteristics of Alport syndrome in Chinese children
AbstractBACKGROUND: Alport syndrome is caused by COL4A3, COL4A4, or COL4A5 gene mutations. The present study aims to compare the clinicopathological features, gene mutations, and outcome of Chinese children with different forms of Alport syndrome. METHODS: One hundred twenty-eight children from 126 families diagnosed with Alport syndrome through pathological and genetic examination between 2003 and 2021 were included in this single-center retrospective study. The laboratory and clinicopathological features of the patients with different inheritance patterns were analyzed. The patients were followed-up for disease progression and phenotype-genotype correlation. RESULTS: Of the 126 Alport syndrome families, X-linked forms accounted for 77.0%, autosomal recessive for 11.9%, autosomal dominant for 7.1%, and digenic for 4.0%. Among the patients, 59.4% were males and 40.6% were females. Altogether, 114 different mutations were identified in 101 patients from 99 families by whole-exome sequencing, of which 68 have not been previously reported. The most prevalent type of mutation was glycine substitution, which was identified in 52.1%, 36.7%, and 60% of the patients with X-linked Alport syndrome, autosomal recessive and autosomal dominant Alport syndrome, respectively. At the end of a median follow up of 3.3 (1.8-6.3) years, Kaplan-Meier curves showed kidney survival was significantly lower in autosomal recessive compared to X-linked Alport syndrome (P = 0.004). Pediatric patients with Alport syndrome seldom presented extrarenal involvement. CONCLUSIONS: X-linked Alport syndrome is the most frequent form found in this cohort. Progression was more rapid in autosmal recessive than in X-linked Alport syndrome.
China National GeneBank DataBase · 2021 · 0 citations · open access
A mouse model for X-linked Alport syndrome induced by Del-ATGG in COL4A5 gene
AbstractAlport syndrome (AS) is an inherited glomerular basement membrane (GBM) disease. X-linked AS (XLAS) is the most common type of AS caused by pathogenic variants in the COL4A5 gene. A mouse model was needed to explore the pathogenesis and progression of the novel frameshift variant c.980_983del ATGG in COL4A5 identified in a male person who was diagnosed with XLAS.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
